3-tetrahydropyranyl ethers of estra-1,3,5(10)-trienes



United States Patent 3,134,771 3-TETRAHYDROPYRANYL ETHERS 0F ESTRA-1,3,5(10)-TRIENES Pietro dc Ruggieri and Carmelo Gandolfi, Milan, Italy,assignors to Ormonoterapia Richter S.p.A., Milan,

Italy, a corporation of Italy No Drawing. Filed Aug. 30, 1962, Ser. No.220,551 Claims priority, application Italy May 12, 1962 6 Claims. (Cl.260-239.55)

This invention relates to new compounds of general wherein R is one ofthe constituents of the group consisting of hydrogen andtetrahydropyranyl and R is one of the constituents of the groupconsisting of hydrogen and of the methyl, ethyl, vinyl and ethinylradicals.

These compounds are endowed with pronounced estrogenic activity and aremore active than the corresponding compounds unprovided with thetetrahydropyranyl group, especially when they are administered by mouth.

To prepare these compounds, the phenolic and alcoholic groups of thesteroids are esterified by means of a treatment with 2, B-dihydropyraneither pure or diluted with suitable solvents, in the presence of anacid catalyst, preferably phosphorus oxychloride or p-toluenesulfonicacid.

The mono-pyranyl phenolic ethers of steroids having an alcoholic groupin position 17 are prepared by reacting thephenol-pyranyl-ethers-l7-ketones with sodium borohydride or lithiumaluminum hydride to obtain l7fi-alcohols, or with potassium acetylide toobtain 17a-ethinyl- 17,8-hydroxy compounds, from which l7oa-vinyl and17aethyl-17 p-hydroxy-steroids are obtained, the former by means of apartial reduction in the presence of pyridine, and the latter by meansof a total reduction.

The following examples are meant to be explanatory only and are in noway to be construed as limiting the invention. I

EXAMPLE 1 Estra-1,3,5(10)Trien-Bis [3-(2'),17fi3-(2")- Tetrahydropyranyloxy] 0.1 part of phosphorus oxychloride are added to asolution of parts of estra-l,3,5(l0)-trien-3, l7 3-diol in a mixture of42 parts of tetrahydrofuran and 12 parts of 2,3-dihydropyran. Themixture is allowed to stand at room temperature for 3 hours and it isthen poured into a mixture of 200 parts of a 5% NaHCO solution and 200parts of ice. The product is collected by filtration and recrystallizedfrom dilute methanol: 5.3 parts of estra- 1,3,5()trien-bis-[3-(2'),l7B-(2" -tetrahydropyranyloxy] are obtained. Theproduct has M.P. 7 6-81 C. and [a] =+21.8 (ethanol).

EXAMPLE 2 17u-Methyl-Estra-1,3,5(10) -Trien-Bis-[3-(2'),17;3-(2")-Tetrahydropyranyloxy] 5 parts of 2,3-dihydropyran and 0.04 part ofphosphorus oxychloride are added to a solution of 2 parts of17amethyl-estra-1,3,5(10)-trien-3,17p-diol in parts of dioxane. Afterstanding for 4 hours at room temperature,

ice

the mixture is poured into 200 parts of a 5% NaHCO solution admixed with200 parts of ice. The product is collected by filtration andrecrystallized from dilute methanol: 2.1 parts ofl7a-methyl-estra-l,3,5(10)-trien-bis-[3-(2),17fi-(2)-tetrahydropyranyl0xy] are obtained. The product has M.P.96-98 C. and [oc] =-l16 (pyridine).

EXAMPLE 3 1 7oc-Ethinyl-Estra-1,3,5 (10 -Trien-Bis- [3- (2' ,17f3- (2"-Tetrahydr0pyranyl0xy] Operating at a temperature of 0 C., 2 parts of17aethinyl-estra-1,3,5(10)-trien-3,17,8-diol are dissolved in 15 partsof 2,3-dihydropyran, and 0.05 part of phosphorus oxychloride are addedto the solution. After standing for 48 hours at room temperature, 200parts of ethyl ether are added and the organic phase is washed with a 5%NaHCO solution and with water. It is then evaporated to dryness undervacuum and the product is recrystallized from petroleum ether: the yieldis 1.92 parts of 17aethinylestra-l,3,5(10)-trien-bis-[3-2'),17B-(2)-tetrahydropyranyloxy], havingM.P. l53155 C. and [11], -24 in pyridine.

EXAMPLE 4 3- (2 '-Tetrahya'r0pyranyloxy 7a-Ethinyl-Estra-. ,3,5 (10-)-Trien-1 7;8-0l.

Four'parts of3-(2'-tetrahydropyranyloxy)-17oc-ethinylestra-1,3,5(10)-trien-17-one aredissolved in a mixture of 34 parts of anhydrous toluene and 260 parts ofanhydrous ethyl ether. The solution is cooled to 0 C. and is kept atthis temperature while it is (l) de-aerated by bubbling a stream ofnitrogen through it for 30 minutes, and then (2) saturated withacetylene. Fifty-six parts of a 14.5% solution of potassium tert.amylate in tert. amyl alcohol are then added over a period of 15 minutesand acetylene is bubbled through the mixture for 5 hours. The mixture isstored overnight at a temperature of 5 C., it is subsequently extractedthree times with 60 parts of a 12.5% NH Cl solution and then washed withwater until neutral. The organic phase is thoroughly dehydrated over NaSO evaporated to dryness and chromatographed on parts of A1 0 From 1:1benzenepetroleum ether eluates, through subsequent recrystallizationfrom dilute methanol, 3.5 parts of3-(2-tetrahydropyranyloxy)-l7a-ethinylestra-1,3,5(10)-trien-l7fi-ol areobtained. The product has M.P. 687l C. and [0:1 :55 in ethanol.

EXAMPLE 5 3 (2'-T etrahydropyranyloxy 7a-Ethinyl-Estra-1,3,5(10)-Trien-1 7fi-0l A solution of3-(2'tetrahydropyranyloxy)-estra-l,3,5 (l0)-trien-l7-one in a mixture of17 parts of toluene and parts of anhydrous ethyl ether is de-aerated bypassing a nitrogen stream through it for 30 minutes, at a temperature of0 C. The solution is subsequently saturated with acetylene. Thirty partsof a 13% solution of potassium tert. butylate in tert. butanol are addedover a period of 15 minutes, and acetylene is kept bubbling for 8 hoursthrough the mixture, which is then stored for 5 days in ice at atemperature of -5 C. The precipitate that has formed is then collectedby filtration, washed with 10 parts of anhydrous ethyl ether, driedunder vacuum, ground in a mortar with 30 parts of a 12% NH Cl solution,again collected by filtration, washed with water until neutral, andfinally recrystallized from dilute methanol. Yield: 1.8 parts of3-(2-tetrahydropyranyloxy)-17a-ethinylestra-l,3,5(10)-trien-17/3-ol,having M.P. 69-71 C. and [a] =-[5.6 in ethanol.

EXAMPLE 6 3- (2'-Tetrahydropyralzloxy -17a-Vinyl-Estra-1,3,5 (10Trien-17B-Ol 1.25 parts of3-(2-tetrahydropyranyloxy)-17u-ethinylestra-1,3,5(10)-trien-17B-ol aredissolved in a mixture of 85 partsof pyridine and 75 parts of dioxane;1.2 parts of palladium-on-calcium carbonate are added, and hydrogenationis carried out under a pressure of 760 rum/Hg. When 84 parts of hydrogenhave been absorbed the catalyst is filtered off, the filtered solutionis evaporated down to a small volume under reduced pressure and fullydiluted with water. The collected product is recrystallized from dilutemethanol and 1.15 parts of3-(2'-tetrahydropyranyloxy)-17a'-vinyl-estra-1,3 ,5 1 -trien- 17 -01 arethus recovered: it has M.P. 57-59 C. and [a] =+50 in ethanol.

EXAMPLE .7

3- (2-Tetrahydropyranyloxy 7a-Ethyl -Estra-1 ,3,5 T rz'en-I 75-01 2parts of3-(2'-tetrahydropyranyloxy)-17a-ethinylestra-1,3,5(10)-trien-17B-ol aredissolved in 100 parts of ethanol and hydrogenated in the presence of 2parts of 5% palladium-on-calcium carbonate. The catalyst is thereafterfiltered off and the solution is concentrated and then diluted withwater. 1.95 parts of 3-(2'-tetrahydropyranyloxy) -17a-ethyl-estra-1,3 ,510) -trien- 175-01 are thus obtained. The product has M.P. 66-68 C. and[u] =+42 in ethanol.

EXAMPLE 8 3 (2 '-T ezrahydropyranyloxy -Estra-1 ,3 ,5 (10 Trien-17fl-OlTwo parts of LiAlH are added to a solution of 10 parts of3-(2-tetrahydropyranyloxy)-estra-1,3,S( 10) -trien-17- one in 50 partsof anhydrous tetrahydrofuran and the mixture is refluxed for 1 hour.

Two parts of ethyl acetate are added to decompose the residual LiAlH themixture is filtered and highly diluted with water. The crude product iscollected by filtration and recrystallized from ethyl ether: 9.2 partsof 3-(2-tetrahydropyranyloxy)-estra-1,3,5,(10)-trien-17fl-ol arerecovered. It has M.P. 147150 C. and [a] =+76 (pyridine).

EXAMPLE 9 3 -(2 '-T etrahydropyranyloxy -estra-1 ,3 ,5 (1 0 Trien-Z -010.6 part of NaBH dissolved in 3 parts of water are added to a solutionof 5 parts of 3-(2'-tetrahydropyranyloxy)-estra-l,3,5(10)-trien-l7-onein 30 parts of methanol and the mixture is refluxed for 1 hour. Water isthen added, the crude product is collected by filtration andrecrystallized from ethyl ether: 4.8 parts of 3-(2-tetrahydropyranyloxy)estra 1,3,5(10) trien 17;? 01 are recovered. It has M.P. 146-148" C. and[oc] =+77 (pyridine).

What we claim is:

1. A compound of the formula:

wherein R is a member selected from the group consisting of hydrogen andtetrahydropyranyl and R is a member selected from the group consistingof hydrogen, methyl, ethyl, and vinyl.

2. Estra -1,3,5(10) -trien bis [3 (2'),17,8 (2")- tetrahydropyranyloxy]3. 17a methyl estra 1,3,5(l0) trien bis [3- (2 1 7B- (2"-tetrahydropyranyloxy] 4. 3 (2 tetrahydropyranyloxy) 17a vinyl estra-1,3 ,5 1O)-trien-17,8-ol.v

5. 3 (2' tetrahydropyranyloxy) 17a ethyl-estra- 1,3,5(10)-trien-17,B-ol.

6. 3 (2 tetrahydropyranyloxy) estra 1,3,5(10)- trien-17,601.

Barton et al June 7, 1960 Nomine et al Ian. 29, 1963

1. A COMPOUND OF THE FORMULA: